Project Summary We propose to investigate the association between circadian system dysfunction, cognition, and Alzheimer?s disease (AD) pathogenesis. Originally, most circadian system changes were thought to be driven by the disease process. Recently, however, there is a growing realization that long-term circadian dysfunction has serious health consequences and may even precede the clinical onset of memory deficits in AD. This field is embarking on a paradigm shift that the circadian system may directly influence AD pathogenesis. Specifically, disruption of the circadian system central pacemaker, the suprachiasmatic nucleus (SCN), may contribute to the observed fragmented circadian system dysregulation in preclinical AD. The goal of this project is to test the hypothesis that poor circadian rhythms mediated by a dysfunctional central clock directly influence AD pathogenesis. The following aims will test this hypothesis: (1) examine the effects of altered SCN function on downstream hippocampal-dependent behavioral, physiological, and molecular rhythms; (2) examine the effects of chronic aberrant SCN signaling on amyloidogenic processes; (3) examine the effects of a circadian intervention on AD pathogenesis. We will combine cutting-edge in vivo optogenetic techniques with sophisticated neurophysiological measures to examine the dynamic regulation of learning and memory processes by the circadian system. Circuit-specific optogenetic manipulation of circadian system function while assaying cognitive functions represents a highly novel and methodologically unique approach. We will decipher a mechanistic link between circadian system dysregulation and cognitive decline in AD. With this project, we are well-poised to uncover new insights into the complex biological mechanisms associated with AD. Because sleep-wake and circadian disruptions are major causes of morbidity and institutionalization among AD patients, we hope that these studies may lead to effective interventions to forestall disease progression, which would also lessen caregiver burden and decrease financial care costs associated with progressing dementia.